Pentose phosphate pathway coordinates multiple redox-controlled relaxing mechanisms in bovine coronary arteries
Pentose phosphate pathway coordinates multiple redox-controlled relaxing mechanisms in bovine coronary arteries
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DOI：
10.1152/ajpheart.00229.2003
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发表时间：
2003-12-01
影响因子：
4.8
通讯作者：
Wolin, MS
中科院分区：
文献类型：
--
作者：
Gupte, SA;Arshad, M;Wolin, MS
用磷酸戊糖途径（PPP）抑制剂6-氨基烟酰胺（6-AN）和表雄酮（Epi）检测去内皮牛冠状动脉（BCA）中NADP（H）氧化还原的变化是否调节收缩力。6-AN（0.01-5 mM）或Epi（1-500 μ M）在用30 mM KCl、0.1 μ M U-44619和内皮素-1收缩的BCA中引起剂量依赖性舒张，但在用佛波醇12，13-二丁酸酯（一种引起Ca 2+非依赖性收缩的蛋白激酶C激活剂）收缩的BCA中不引起。PPP抑制的松弛与NADPH和谷胱甘肽（GSH）的氧化有关。对6-AN的松弛不受H2 O2介导，因为它不受缺氧或过氧化物清除剂依布硒啉（100 μ M）的影响。巯基还原剂DTT（3 mM）使对6-AN和Epi的松弛减弱30- 40%。糖酵解或线粒体电子传递的抑制没有引起与30 mM KCl收缩的BCA松弛，这表明这些途径可能不参与PPP抑制引起的松弛。高剂量的K+通道阻滞剂[例如，TEA（10 mM）和4-氨基吡啶（10 mM）]仅部分抑制对6-AN的松弛。Fura-2荧光比率的变化的基础上，6-AN和Epi出现显着降低细胞内Ca 2+。因此，PPP抑制氧化NADPH和GSH，并似乎激活一种新的协调的氧化还原控制的放松机制，主要通过减少细胞内Ca 2+介导的BCA。
Pentose phosphate pathway (PPP) inhibitors, 6-aminonicotinamide (6-AN) and epiandrosterone (Epi), were employed to examine whether changes in NADP(H) redox regulates contractile force in endothelium-removed bovine coronary arteries (BCAs). 6-AN (0.01-5 mM) or Epi (1-500 muM) elicited dose-dependent relaxation in BCAs contracted with 30 mM KCl, 0.1 muM U-44619, and endothelin-1 but not with phorbol 12,13-dibutyrate, a protein kinase C activator that causes Ca2+-independent contraction. Relaxation to PPP inhibition was associated with oxidation of NADPH and glutathione (GSH). Relaxation to 6-AN was not mediated by H2O2, because it was not altered by hypoxia or the peroxide scavenger ebselen (100 muM). The thiol reductant DTT (3 mM) attenuated the relaxation to 6-AN and Epi by 30-40%. Inhibition of glycolysis or mitochondrial electron transport did not elicit relaxation in BCAs contracted with 30 mM KCl, suggesting these pathways may not be involved in relaxation elicited by PPP inhibition. High doses of K+ channel blockers [e.g., TEA (10 mM) and 4-aminopyridine (10 mM)] only partially inhibited the relaxation to 6-AN. On the basis of changes in the fura-2 fluorescence ratio, 6-AN and Epi appeared to markedly reduce intracellular Ca2+. Thus PPP inhibition oxidizes NADPH and GSH and appears to activate a novel coordination of redox-controlled relaxing mechanisms in BCAs mediated primarily through decreasing intracellular Ca2+.